This application aims to explore a novel strategy in suppressing prostate cancer metastasis. The strategy is to use small double-strand RNA molecules, which are complimentary to gene promoter, to enhance gene transcription. These RNA molecules are termed as small activating RNA (saRNA). We will use them to target the promoter of collapsin response mediator protein-4 (CRMP4) gene, a recently identified metastatic suppressor in prostate cancers. The candidate saRNA molecules with high potency will be fused to a prostate cancer-specific Aptamer, a RNA molecule that specifically binds to prostate specific membrane antigen for delivery. We will also study the mechanism of CRMP4-mediated metastasis suppression. Metastasis is the major cause of cancer death and locally advanced high-risk prostate cancers with positive surgical margin and high grade tumors are often times develop rapid recurrence and systemic metastasis. In a search for protein biomarkers associated with metastatic prostate cancers, we identified CRMP4 as a metastasis suppressor in prostate cancers. Its expression is dramatically low in metastatic lymph nodes compared to primary tumors and its over-expression in prostate cancer cells not only suppressed cell motility/invasion in vitro but also strongly inhibited tumor metastasis in animal xenograft model. Thus, we hypothesized that enhancing CRMP4 expression in high-risk prostate cancers will suppress tumor metastasis. Recent emerging evidence showed that saRNAs targeting gene promoters are potent in inducing prolonged gene activation at the transcriptional level. Several reports have demonstrated the potential usage of double- stranded RNAs targeting tumor suppressor genes in inhibiting tumor cell growth in vitro and in vivo. The objective of this application is to develop and validate multiple saRNAs targeting CRMP4 promoter for suppressing metastasis of prostate cancer. The rationale is based on our recent publication and preliminary studies, as well as previous reports from other groups. We believe that its successful completion of this project would lead to a novel therapy for prostate cancers or even a cure when used with other chemo-reagents for this health-threatening disease.